This invention relates to novel peptides possessing potent natriuretic and diuretic activity and sharing sequence homology with portions of the N-terminal fragment (NTF) of the pituitary prohormone proopiomelanocortin (POMC). Similar or identical peptide(s) may function as hormone(s) involved in the physiological regulation of body water and electrolyte balance. In addition, this invention relates to a process for the production of the novel compounds and to pharmaceutical compositions containing said peptides as free acids, as amides or as salts in combination with a pharmaceutically acceptable carrier or diluent, and to the use of such compositions as natriuretic, diuretic or antihypertensive agents in the treatment of congestive heart failure, hypertension and other disturbances of water and electrolyte balance.
POMC, is the precursor molecule of ACTH or corticotropin, the pituitary hormone which regulates production of the glucocorticoid hormone cortisol by the adrenal cortex, as well as of several other biologically active peptides including beta-lipotropin, alpha- and beta-melanotropin, and beta-endorphin. In high concentrations, all of these peptides are capable of stimulating secretion of the mineralocorticoid hormone aldosterone in vitro or in vivo suggesting that they may play a role in the physiological regulation of volume and blood pressure homeostasis, although direct proof for this hypothesis is lacking. While all of these peptides are derived from the mid- and C-terminal portions of the POMC molecule, POMC also contains a large N-terminal fragment of more than 70 aminoacids whose physiological function is still uncertain. Wiedemann ct al. (1982, Program, Seventh Asia and Oceania Congress of Endocrinology, p. 88), synthesized an NTF-midregion peptide, namely NTF[32-49], raised antisera to it and developed a radio-immunoassay suitable to measure NTF midregion-like peptides. Employing this assay to measure NTF midregion-like immunoreactive material (IR-NTF) in plasma in an animal model of natriuresis, the acutely uninephrectomized rat, a consistent positive correlation was observed between the amount of sodium excreted and the plasma concentration of IR-NTF; experimental maneuvers that blocked the rise of IR-NTF also blocked the natriuresis (Lin et al., 1985, Am. J. Physiol. 249, F282; Lin et al., 1987, Am. J. Physiol. 252, F276). These results suggested, but did not prove, promotion of natriuresis by NTF or NTF derived peptides. Neither intact NTF nor peptides derived from the midportion of NTF have previously been shown to affect diuresis or sodium excretion.
We have discovered and now disclose that peptides containing the aminoacid sequence NTF[37-49] possess potent natriuretic and diuretic properties.